S269: MALE PATIENTS WITH SCD HAVE A HIGHER RISK OF CEREBROVASCULAR DISEASE, INCREASED INFLAMMATORY MARKERS, AND POORER RESPONSE TO HYDROXYUREA
Authors: Margherita DI Mauro, Amina Nardo‐marino, Sara Stuart-Smith, Sara El Hoss, John Strouboulis, Stephan Menzel, John Gibson, David Rees, John Brewin
Journal: HemaSphere (2023)

Background: Sickle cell disease (SCD) is a disorder with myriad clinical manifestations. The clinical variability is determined by multiple factors, including biological sex. Aims: We examined a large cohort of adults and children with HbSS and HbSC, to review the effects of sex on a range of laboratory measurements and clinical parameters with the aim to extend our understanding of sex differences in SCD outcomes. Methods: The King’s College Hospital (London, UK) patient record system was used to collect clinical and laboratory data, from October 2008 to October 2020. This study was ethically approved, and written consent obtained from all participants. All blood results were taken at steady-state, with no blood transfusion within 90 days. Analysis of variance was used to test the association of sex against all clinical laboratory measurements. For patients with laboratory data before and during hydroxyurea (HU) therapy, unpaired T tests were used to compare response based on sex. Analysis of stroke outcomes included age of event and co-inheritance of α-thalassemia as covariates in cox-proportionate hazards models and Kaplain-Meier plots. Results: A total of 802 individuals with HbSS (median age 35.1 years, 54% female) and 267 with HbSC (median age 45 years, 64% female) were included in the study. Male sex was associated with increased hemoglobin (Hb), haematocrit and absolute reticulocyte count (ARC) in both HbSS and HbSC. Fetal hemoglobin (HbF) levels were significantly higher in females with HbSS compared to males (p= 6.9E-12). Males with HbSS had increased inflammatory markers compared to females, with elevated monocytes (p= 3.9E-08), eosinophils (p= 0.00043) and C-reactive protein (p= 4.4E-06). Liver function test and estimated glomerular filtration rate were increased in males with HbSS, but not HbSC. Data from 171 patients with HbSS before and during HU therapy were analysed. The increase in HbF, total Hb and mean corpuscular volume during HU treatment was significantly higher in females than males (respectively p= 0.00098, p= 0.046, p= 0.012). Kaplan-Meier plots showed that males had a higher incidence of all adverse cerebrovascular outcomes compared to females (Figure 1). Males had a higher hazard for overt ischemic strokes (1.4, 95%CI 0.89-2.2, p=0.135), for large vessel disease (1.5, 95%CI 1.04-2.17, p=0.028) and for silent cerebral infarcts (1.55, 95%CI 1.2-2.03, p= 0.002), but no significant sex difference in Transcranial Doppler velocities performed in childhood. We observed an increase in the average number of hospitalisations per year (p= 0.04) and in the average number of transfusions per year (p= 0.029) for males with HbSS, but no difference in HbSC. Finally, we reported the survival analysis of almost 900 patients. The median survival in individuals with HbSS was 62 years and in HbSC was 80 years. Sex had no effect on survival in either cohort (p= 0.77). Summary/Conclusion: In our study population, males with HbSS had worse disease outcomes in almost all SCD aspects compared to females. Males had higher ARC, increased markers of inflammation, more abnormal liver and renal function, lower HbF levels, poorer response to HU, increased number of hospital admissions and blood transfusions, and an increased risk of cerebrovascular disease. However, males did have higher Hb, usually associated with a milder phenotype, and no difference in overall survival was observed. Overall, sex has a significant effect on many aspects of SCD. Understanding better how sex affects the pathophysiology of SCD will ultimately lead to improved clinical management.Keywords: Cerebrovascular disease, Sickle cell disease